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Purpose: Hearing loss (HL) is a genetically heterogeneous common neurosensory disorder. Among different ethnic groups, pathogenic variants of Myosin XVa (MYO15A) at the DFNB3 locus are the common causes of autosomal recessive nonsyndromic hearing loss (ARNSHL). The aim of this study was to determine the prevalence and the type of MYO15A pathogenic variants in a subset of Iranian pedigrees with ARNSHL. Materials and Methods: Thirty-eight Iranian pedigrees with no Gap junction beta-2 pathogenic variants were included in the study. For all pedigrees, linkage analysis was performed using five short tandem repeat markers of DFNB3 locus. The DNA sequencing was then applied to identify MYO15A pathogenic variants in linked pedigrees. Results: Altogether, two out of 38 (5.3%) pedigrees were linked to locus 3. After sequencing, five previously unreported MYO15A pathogenic variants (c.1775-1776insA, c.1766-1767insC, c.7694delA, c.611G > C (G204A), and c.6442T > A (W2148R)) were revealed in homozygous and heterozygous state in the two pedigrees studied. Furthermore, the pathogenicity of pathogenic variants was confirmated by Insilco and cosegregation analysis in this study. Conclusions: Our findings support a relatively high prevalence and specificity of MYO15A pathogenic variant among Iranian ARNSHL patients. Molecular study of MYO15A may lead to elucidation of the population-specific pathogenic variant profile, which is of importance in molecular diagnostics of HL. [ABSTRACT FROM AUTHOR]

Background and Objectives: Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported.Methods: A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease.Results: NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family.Conclusions: The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family.Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease.Results: WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines.Conclusions: Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients. [ABSTRACT FROM AUTHOR]

Background: Hearing loss (HL) is one of the most common sensory disorders (1/1000). Various studies have shown that a large proportion of autosomal recessive nonsyndromic HL (ARNSHL) in Iranian populations is caused by defects in a certain number of genes; new detection methods such as sequencing of the exome (exome-sequencing) can increase the frequency identification of responsible mutations for HL. The aim of this study was to screen for ARNSHL pedigrees and to find the responsible genes. Materials and Methods: Fifty big ARNSHL pedigrees including 130 Iranian patients with ARNSHL took part in this study. Direct sequencing and multiplex polymerase chain reaction were, respectively, used for the presence of GJB2 and GJB6 (del D13S1830 and del D13S1854) mutations in all of the families. The negative pedigrees for these genes were tested to homozygosity mapping for the linkage to nine known loci, then the negative pedigrees for them were sent for exome-sequencing. Results: Nine of 50 pedigrees had GJB2 (18%) mutations. No GJB6 mutation was found. Totally, 11 of 50 pedigrees (22%) showed linkage to 6 known loci DFNB, including 2 pedigrees to DFNB2, 2 pedigrees to DFNB3, 2 pedigrees to DFNB4, 2 pedigrees to DFNB7/11, 3 pedigrees to DFNB12, and 2 pedigrees to DFNB104. An individual from a large pedigree was examined by exome-sequencing and was observed no changes. Conclusion: In this study, DFNB1 and DFNB12 are the main causes of ARNSHL. GJB6 mutations, DFNB6, and DFNB59 were absent. Therefore, 40% of the ARNSHL etiology was found in this study. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) is the most common birth defect and the most prevalent sensorineural condition worldwide. It is associated with more than 1,000 mutations in at least 90 genes. Mutations of the gap junction beta‐2 protein (GJB2) gene located in the nonsyndromic hearing loss and deafness (DFNB1) locus (chromosome 13q11‐12) are the main causes of autosomal recessive nonsyndromic hearing loss worldwide, but important differences exist between various populations. In the present article, two common mutations of the GJB2 gene are compared for ethnic‐specific allele frequency, their function, and their contribution to genetic HL in different populations. The results indicated that mutations of the GJB2 gene could have arisen during human migration. Updates on the spectrum of mutations clearly show that frequent mutations in the GJB2 gene are consistent with the founder mutation hypothesis. [ABSTRACT FROM AUTHOR]

miRNAs are important factors for post-transcriptional process that controls gene expression at mRNA level. Various biological processes, including growth and differentiation, are regulated by miRNAs. miRNAs have been demonstrated to play an essential role in development and progression of hearing loss. Nowadays, miRNAs are known as critical factors involved in different physiological, biological, and pathological processes, such as gene expression, progressive sensorineural hearing loss, age-related hearing loss, noise-induced hearing loss, cholesteatoma, schwannomas, and inner ear inflammation. The miR-183 family (miR-183, miR-96 and miR-182) is expressed abundantly in some types of sensory cells in inner ear specially mechanosensory hair cells that exhibit a great expression level of this family. The plasma levels of miR-24-3p, miR-16-5p, miR-185-5p, and miR-451a were upregulated during noise exposures, and increased levels of miR-21 have been found in vestibular schwannomas and human cholesteatoma. In addition, upregulation of pro-apoptotic miRNAs and downregulation of miRNAs which promote differentiation and proliferation in age-related degeneration of the organ of Corti may potentially serve as a helpful biomarker for the early detection of age-related hearing loss. This knowledge represents miRNAs as promising diagnostic and therapeutic tools in the near future. [ABSTRACT FROM AUTHOR]

Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) is the most common sensory-neural disorder with excessive clinical and genetic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of the disease with no specific genotype-phenotype correlation in most of the cases. Whole exome sequencing (WES) is a powerful tool to overcome the problem of finding mutations in heterogeneous disorders. A comprehensive clinical and pedigree examination was performed on a multiplex family from Khuzestan province suffering from hereditary HL. Direct sequencing of GJB2 and genetic linkage analysis of DFNB1A/B was accomplished. WES was utilized to find possible genetic etiology of the disease. Co-segregation analysis of the candidate variant was done. High resolution melting analysis was applied to detect variant status in 50 healthy matched controls. Clinical investigations suggested ARNSHL in the pedigree. The family was negative for DFNB1A/B. WES revealed a novel nonsense mutation, c.256G > T (p.Glu86*), in TMC1 segregating with the phenotype in the pedigree. The variant was absent in the controls. Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL in a large family. The novel nonsense TMC1 variant meets the criteria of being pathogenic according to the ACMG-AMP variant interpretation guideline. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) is the most common sensorineural disorder and one of the most common human defects. HL can be classified according to main criteria, including: the site (conductive, sensorineural and mixed), onset (pre-lingual and post-lingual), accompanying signs and symptoms (syndromic and non-syndromic), severity (mild, moderate, severe and profound) and mode of inheritance (Autosomal recessive, autosomal dominant, X-linked and mitochondrial). Autosomal recessive non-syndromic HL (ARNSHL) forms constitute a major share of the HL cases. In the present study, next-generation sequencing (NGS) was applied to investigate the underlying etiology of HL in a multiplex ARNSHL family from Khuzestan province, southwest Iran. In this descriptive study, 20 multiplex ARNSHL families from Khuzestan province, southwest of Iran were recruited. After DNA extraction, genetic linkage analysis (GLA) was applied to screen for a panel of more prevalent loci. One family, which was not linked to these loci, was subjected to Otogenetics deafness Next Generation Sequencing (NGS) panel. NGS results showed a novel deletion-insertion variant (c.1555delinsAA) in the MARVELD2 gene. The variant which is a frameshift in the seventh exon of the MARVELD2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. NGS is very promising to identify the molecular etiology of highly heterogeneous diseases such as HL. MARVELD2 might be important in the etiology of HL in this region of Iran. • Two panels of deafness genes based on linkage and next-generation sequencing (NGS) were used. • A novel insertion variant was identified in the MARVELD2 gene (DFNB49). • This study proves the application of the NGS in the study of such heterogeneous disorders as hearing loss • Our study is the second study which shows DFNB49 HL in Iran. • The results might suggest that MARVELD2 mutations should be considered in the diagnosis of hearing loss in Iran. [ABSTRACT FROM AUTHOR]

Abstract Objective Mutations in the GJB2 gene are a major cause of autosomal recessive non-syndromic HL (ARNSHL) in many populations. Previous studies have estimated the average frequency of GJB2 mutations to be between 16 and 18% in Iran, but would vary among different ethnic groups. Here, we have taken together and reviewed results from our three previous publications and data from search other published mutation reports to provide a comprehensive collection of data for GJB2 mutations and HL in the south of Iran. Methods In all, 447 unrelated families were included and analyzed for the prevalence and type of the GJB2 gene mutations. Results Totally, the frequency of GJB2 mutations was found to be 11.5% in the southern provinces studied which is significantly lower than that identified in Northern populations of Iran, and also a southwest to southeast Iranian gradient in the frequency of GJB2 mutations is suggested. Conclusions This study highlights the importance of establishing prevalence, based on the local population for screening and diagnostic programs of live births in Iran. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Autosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL. Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. Methods: We examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. Results: Sequence analysis of GJB4 showed five heterozygous variations including c.451C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. Conclusion: Our data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern. [Copyright &y& Elsevier]